The present invention relates to enteric-soluble preparations.
Enteric-soluble preparations are normally prepared using a film-forming substance which is soluble in the intestinal juices. The pH value at which commercially available film-forming substances dissolve is about 6.8, which means that enteric-soluble preparations made of such a film-forming substance should also disintegrate at about pH 6.8. However, there is a need for enteric-soluble preparations that will disintegrate at pH values below 6.8, and particularly values in the range from 3 to 6, since the pH value in the duodenum after a meal is normally about 3.5 and because the pH values in the stomach and intestines vary from time to time in each individual and also vary between individuals.
No available film-forming substance appears to meet this requirement.
The bioavailability of known enteric-coated preparations varies significantly at each administration between individuals or even in the same individual, both in terms of the quantity released and the rate of release of the active component; this contrasts with conventional preparations administered orally, where amounts and rate of release are reasonably predictable. This inevitably gives rise to uncertainties as to the effectiveness of enteric-coated preparations. Moreover, it is a common observation that the average bioavailability of enteric-coated preparations is lower than that of other preparations. This is partly because of variations in the pH in the digestive organs between individuals or in the same individual but at different times and partly because it is difficult to be certain that the enteric-soluble membrane surrounding the preparation will dissolve, disperse or disintegrate sufficiently rapidly and certainly in the digestive organs, particularly in the small intestines.
For example, if a drug is administered in a single enteric-soluble unit dose (e.g. a tablet), which can be absorbed only in the upper small intestine, bioavailability will be 0% if, for any one of many reasons, the dose does not happen to disintegrate in the upper small intestine and, as a result, the drug may not be utilised at all. In order to avoid this risk, administration is sometimes effected by means of a large number of small unit doses (for example a number of enteric-soluble granules contained together in a conventional capsule). Administration in this way, however, means that at each administration the bioavailability is the average of the actual bioavailabilities of the individual granules, which is therefore less than the theoretical maximum of 100%. Accordingly, although this expedient has the effect of ensuring the there is a reasonable likelihood that at least some of the active ingredient given with each administration is utilised, it does not improve the overall average bioavailability.
The reasons for administering drugs orally in the form of enteric-soluble preparations can be summarised as follows:
(1) prevention of decomposition of drugs that are unstable at pH values lower than a certain level;
(2) prevention of side effects brought about by the release of drugs in the stomach;
(3) prevention of dilution of drug concentration in the intestines, attributable to disintegration of drugs in the stomach and their subsequent movement to the intestines; and
(4) prolonged effect.
Although such preparations are referred to generally as "enteric-soluble preparations", there are, in fact, various types depending upon their functional requirements, as the object of using them can be different, as described above. Thus, they can be divided into the following types:
A. Those that do not release drugs in the stomach, that is to say, the enteric-soluble preparations which do not undergo dissolution, dispersion or disintegration at the pH value in the stomach of an ordinary person, and the drug is not released in the stomach through the membrane of the preparation.
B. Those that do not need to specify the site at which disintegration takes place; these preparations will not undergo dissolution, dispersion or disintegration at pH values below a specified value, and outside liquids will not permeate into such preparations through the membrane, but they do undergo dissolution, dispersion or disintegration of pH values higher than this specified value.
C. Those that undergo dissolution, dispersion or disintegration at a specified site, particularly at a specified site in the intestines, regardless of the pH value.
Of these three types of preparations, quite special ones are known for type C; these special preparations are monitored from outside the body after administration (e.g. by X-ray projection) to determine their position in the digestive organs and, when they reach the desired site, the drugs contained therein are released by the joint action of an electro-magnetic pulse emitted from outside the body and of the counterpart receiver contained in the preparation. The present invention is not aimed at such special types of preparations but at enteric-soluble preparations of types A and B.
As regards the pH value in the digestive organs, the following is known from the literature:
1. pH in the stomach
The pH value in the stomach of an ordinary person after a meal is 1.67. It reaches 3.0 at the highest, even when all the acid is combined with protein. (Howell, W. H., "A Textbook of Physiology", 13th ed., Saunders, Philadelphia, 1938, page 82, 858).
The pH value in the stomach of 137 persons who had no history of stomach disease or anaemia was determined. 65% were in the range pH 1.5-2.5 and 86% were in the range pH 1.5-3.5 after having a proteinaceous meal. [Levin, E., et al., J. Lab. Clin. Med., 38, 828 (1951); Bernstein, R. E., ibid., 40, 707 (1952)].
The pH value in the stomach of a human is normally between 1 and 3.5, mostly between 1 and 2.5. (Wagner, J. G., "Biopharmaceutics and Relevant Pharmacokinetics", 1st Ed., Hamilton Press, Illinois, 1971, page 3).
The pH value in the stomach after a meal is controlled by itself by virtue of a feed-back mechanism. Namely, the release of gastrin to the blood stops at a pH value below 1.8-2.0 and reaches the maximum at a pH value above 3.0. (Yoshitoshi, Y., et al, "Biochemistry of Diseases, Vol. 13B, Digestive Organs", Nakayama Shoten, Tokyo, 1976, page 3).
The pH value in the empty stomach of 83 patients (64 males and 19 females, of whom 17 were healthy; of the remainder, there were 43 cases of chronic gastritis, 39 cases of gastric ulcers, 10 cases of duodenal ulcers, and 5 cases of gastric tumours) was determined with an antimony electrode capsule for the pH measurement. All values fell within the range of 0.2-2.5. (Kawai, K., "Stomach, Its Shape and Function", Igaku Shoin, Tokyo, 1975, page 83).
2. pH in the small intestine
The pH value in the small intestine is normally from 5 to 7. It goes up along the intestine and may reach 7-8 in the lower small intestine. (Wagner, J. G., op. cit. page 3).
The pH value in the empty duodenum is about 6.5, whereas it is about 3.5 after a meal. (Yoshitoshi. Y, et al., op. cit. page 8).
In view of the above-mentioned literature, it would appear that the properties required for type A enteric-soluble preparations are such that they are resistant to dissolution, dispersion or disintegration at pH values below 3.0 or perhaps 4.0 but are susceptible at a pH value slightly higher than 4.0. Further consideration should be given, however, to cases in which release of drugs in the stomach should be avoided as much as possible, or to those individuals having less acid in their stomachs, where the pH value may be about 5. In these cases, the pH value at which rapid dissolution, dispersion and disintegration take place should be designed to be much higher.
The pH value of artificial enteric juice, as prescribed in the Pharmacopoeias of many countries is about 7.0. However, for the reasons mentioned above, this does not fully comply with practical requirements. Rather, it is considered preferable to design for enteric-soluble preparations to disintegrate at a pH value as low as 6.0 in view of the information noted above.
Further, in order to ensure the bioavailability of drugs whose absorption site is limited, for instance, to the upper intestine, it is quite insufficient only to ensure that they dissolve, disperse or disintegrate at pH 6, in view of the pH values in the duodenum, namely about 3.5 after a meal, as described above. Therefore, it is considered desirable for type B preparations to dissolve, disperse or disintegrate rapidly at the lowest possible pH value within the permissible range.
For these reasons, enteric-soluble preparations should be designed to disintegrate as quickly as possible at any pH value between 3 and 6, and it is an object of this invention to provide such enteric-soluble preparations. In other words, it is to provide preparations (and specifically the membrane thereof) that would not allow outer liquid to permeate into the preparations or allow the drugs to release themselves through the membrane at a pH value lower than 1-2, but which dissolve, disperse or disintegrate at any pH value higher than this.
Disintegration of enteric-soluble base polymers so far known was examined and, as a result, it was found to be insufficient at pH values lower than 6.0 with almost all polymers.